The antiepileptic drug lamotrigine is approved by the FDA for the treatment of epilepsy and maintenance treatment of bipolar I disorder. The drug is considered particularly effective in the prevention of bipolar depressive episodes.1,2 Lamotrigine is generally well tolerated; however, it carries a risk for a severe or life-threatening skin rash. Although approximately 8% to 10% of individuals exposed to lamotrigine develop a skin rash, the incidence of severe rashes is estimated to be 0.08% (monotherapy) to 0.13% (adjunctive therapy) in adults.3-5
Antiepileptic drugs can be classified by the presence of an aromatic ring in the chemical structure. This aromatic ring has been hypothesized to be responsible for the increased risk for cutaneous hypersensitivity reactions.6 Antiepileptic drugs with an aromatic ring include carbamazepine, phenytoin, phenobarbital, and lamotrigine. Nonaromatic antiepileptic drugs include levetiracetam, gabapentin, and valproate. In a large meta-analysis, Wang and colleagues determined that the risk of rash from lamotrigine was greater than the risk from nonaromatic antiepileptic drugs but was not significantly different compared with other aromatic antiepileptic drugs.4
Lamotrigine rashes are typically allergic in nature, presenting as simple, benign morbilliform rashes with onset between 5 days and 8 weeks after treatment initiation; the rashes tend to disappear within a few days after the medication is stopped. More serious reactions include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and antiepileptic drug hypersensitivity syndrome (AHS).
Serious drug rashes are usually widespread; include prominent facial, neck, and upper trunk involvement; may be tender or have a hemorrhagic appearance that does not blanch with pressure; and may be accompanied by signs and symptoms of internal toxicity.3,5
Ms. B, 35, was referred to outpatient psychiatry by her therapist for evaluation and treatment of symptoms of depression, which included depressed mood and irritability, insomnia, fatigue, poor concentration, thoughts of harming herself and others, and a breakdown in her functioning at work and home. Her history was significant for several similar episodes of depression that were treated with a variety of antidepressants.
Ms. B's self-reported response to the antidepressants ranged from nonresponse (bupropion, vilazodone) to partial response (escitalopram), and one adverse cutaneous drug reaction (sertraline). The patient was restarted on escitalopram at her request, as it had the fewest adverse reactions and was the most beneficial.
Ms. B's depressive symptoms worsened over approximately 4 weeks of treatment with escitalopram. Upon further evaluation, she could describe a history of discrete hypomanic episodes lasting 4 to 5 days with racing thoughts, elevated energy, decreased need for sleep, increased creativity and goal-directed activities, and increased irritability toward coworkers. These episodes had never required hospitalization and had resolved without treatment.
A history of major depressive episodes and hypomanic episodes is consistent with a diagnosis of bipolar II disorder.7 Treatment of bipolar II disorder is closely aligned with that of bipolar I disorder and depends on the phase of illness (hypomania or depression). Current best practice guidelines recommend lamotrigine or quetiapine as the most effective monotherapies for treatment of bipolar II disorder.8 These drugs have excellent antidepressant effects and can be continued after remission of mood episodes to prevent relapse and recurrence. Lamotrigine and quetiapine have FDA-approved indications for the treatment of bipolar I disorder. Generally, mood stabilizers are the first choice over antipsychotics. Ms. B was therefore started on lamotrigine 25 mg daily with a plan to titrate slowly up to a therapeutic dose. Within 3 days after starting the lamotrigine, Ms. B was hospitalized for 5 days due to continued suicidal ideation. The hospital staff continued the same medications without raising the dosage of lamotrigine.
When Ms. B returned to the outpatient clinic, she had been taking escitalopram 10 mg and a starting dose of lamotrigine 25 mg daily for 4 weeks. Lamotrigine was increased to 50 mg daily and was titrated slowly up to a therapeutic dosage of 200 mg daily over the next month. Unlike her response to antidepressants, Ms. B achieved full remission of depressive symptoms after 2 months of taking lamotrigine.
Three months after starting lamotrigine, Ms. B complained of a pruritic rash that had started while in the hospital on her left thigh and had spread to the right calf and thigh. Although she had been instructed to report any occurrence of skin rash, Ms. B had dismissed the rash as insignificant. The location of the rash was widespread but localized to the lower extremities and unaccompanied by any systemic symptoms, such as fever, malaise, angioedema, or pharyngitis. On exam, Ms. B had no lymphadenopathy, hepatosplenomegaly, or postpharyngeal erythema. The pulmonary and cardiovascular exam was within normal limits.
Diagnostic focus and assessment
Due to the size (larger than 30 cm) and distribution of the rash, a referral was made to a collaborating dermatologist. The dermatologist described the rash as a hyperpigmented patch with subtle erythematous thin planar plaques (see Hyperpigmented patch). The presentation was not consistent with SJS, TEN, DRESS, or AHS. In addition, Ms. B had a mottled annular patch on her right lower leg.
A punch biopsy of the right thigh lesion showed mild superficial perivascular lymphocytic infiltrate with occasional perivascular and interstitial eosinophils...consistent with a mild spongiotic drug eruption. The dermatologist recommended treating the rash with a topical corticosteroid cream (fluocinonide 0.05%). The dermatologist saw no reason to discontinue the lamotrigine, so Ms. B continued taking the medication.
Within 1 week of her dermatology evaluation, Ms. B noted a new large, pruritic lesion on her right thigh. A decision was made to decrease the lamotrigine from 200 mg to 50 mg and refer her to an allergist for another opinion. The allergist saw her within 5 days and determined, by visual inspection and review of the previous biopsy report, that the rash was atypical for urticaria but had some resemblance to erythema multiforme consistent with hypersensitivity response. Lab findings were benign apart from a mildly elevated erythrocyte sedimentation rate (ESR) and the liver enzyme aspartate aminotransferase (AST). The allergist recommended discontinuing lamotrigine, and Ms. B was tapered off.
Follow-up and outcomes
Ms. B's rash resolved within 10 days after discontinuing lamotrigine; however, a new episode of mood instability/irritability, interpersonal reactivity and anger outbursts, racing thoughts, insomnia, and difficulty functioning at work returned within the next 2 weeks. After reviewing her options (and Ms. B's preference to avoid lithium and antipsychotics), she was started on a second antiepileptic drug mood stabilizer (divalproex sodium), which is particularly effective in the treatment of manic and hypomanic episodes and can be continued for maintenance.9 Divalproex was started and the oral dose titrated up to 250 mg twice daily. The medication was well tolerated, with further mood stabilization over a 2-week period. For greater convenience, Ms. B was shifted to the oral extended-release formulation, divalproex ER.
Within 1 day, Ms. B noticed a new rash on her right inner thigh and forearm. The drug was immediately discontinued and switched back to the twice-daily formulation. The rash gradually subsided over the next 2 weeks with the addition of over-the-counter cetirizine, recommended for allergic reaction. Ms. B's mood remained stable, and she experienced a resolution of mood and behavioral symptoms. The mood stability was continued at 4- and 8-week follow-ups.
Self-reported Patient Health Questionnaire (PHQ-9) scores corroborated her clinical presentation, beginning with a high score of 27 prior to hospitalization, improving to 7 with lamotrigine treatment, and stabilizing at 11 after 8 weeks on divalproex. Although Ms. B felt better on the lamotrigine, she felt stable with mild residual depressive symptoms and good overall functioning on divalproex.
In this case, rather than a severe cutaneous adverse drug reaction (SJS, TEN, DRESS, AHS), the patient was diagnosed as having a mild allergic response, which responded well to topical corticosteroids and antihistamines. Ms. B's rash began within 1 week of starting lamotrigine and subsided within 10 days, as would be expected for a benign allergic response to lamotrigine.10
Notably absent in Ms. B's presentation were signs and symptoms of systemic involvement, including angioedema, pharyngeal erythema, facial/trunk rash, fever, hepatomegaly, subjective reports of malaise and anorexia, and lab findings indicating systemic organ involvement. Minor elevations in ESR and AST were more consistent with a mild inflammatory response than with organ or systemic involvement, and these eventually returned to baseline levels.
Ms. B was able to successfully tolerate the nonaromatic antiepileptic drug divalproex. Her cutaneous responses to lamotrigine and divalproex ER were similar to a previous reaction to the antidepressant, sertraline. Her pattern of developing adverse cutaneous reactions to multiple drugs places her at a higher risk for drug intolerance or hypersensitivities.11
After several months of treatment with divalproex, the patient complained of fatigue and headaches that were impairing her work, and she was eventually switched to quetiapine. Ms. B had no recurrence of serious mood episodes requiring hospitalization and continued to function well without subjective adverse reactions. She was regularly assessed for long-term metabolic effects.
Implications for practice
Bipolar II disorder is a serious mental illness that can be life threatening. Lamotrigine is one of the two medications recommended by current best practice guidelines for the long-term management of the disorder.8 Lamotrigine is generally a well-tolerated medication that is especially effective in the treatment of bipolar depression and prevention of relapse or recurrence.
In Ms. B's case, once the medication was titrated to a therapeutic level, she had a favorable response to the medication. The development of a rash was a disappointing turn of events. A consultant dermatologist and allergist were in agreement that Ms. B had a mild allergy/hypersensitivity to the lamotrigine.
According to the FDA, it is not possible to predict which rashes will be serious or life threatening; therefore, lamotrigine should be discontinued at the first sign of rash unless the rash is clearly not drug-related.12 The authors opted, in collaboration with Ms. B, to discontinue the drug, and she was able to restabilize on another antiepileptic drug and eventually transition to long-term maintenance treatment with the second generation antipsychotic quetiapine.
The diagnostic distinction between mild and severe adverse cutaneous drug reactions is important for treatment decisions. Drugs that cause severe systemic reactions should not be used again, drugs that cause a benign rash are relatively contraindicated, and drugs that cause unpleasant adverse reactions may be safe.13 If a drug is important for a patient's health but causes a benign rash, there may be ways to reduce sensitivity and continue treatment.
Recent systematic reviews of the literature indicate that lamotrigine rechallenge is successful in over 70% of patients.3,14,15 If a rash develops during the first 8 weeks of lamotrigine therapy, the provider should hold the next dose, pending evaluation by a specialist.3 If the rash shows cutaneous features of a severe reaction or is associated with systematic symptoms, it should be promptly discontinued to reduce the consequences of a potentially life-threatening reaction.3 Through future larger studies, the decision of whether to rechallenge a patient who has experienced a benign cutaneous adverse reaction from lamotrigine will be increasingly clear.
This case highlights some important points. First, many medications can have cutaneous adverse reactions in the form of simple or more systemic rashes, which can range from minor to life threatening. These skin reactions are particularly common to antiepileptic medications. In the case of a non-life-threatening rash, a variety of modalities can be employed, along with an assessment of the efficacy of the original offending drug, in order to weigh the risks versus benefits of various options.
Offending agents can be discontinued or cautiously continued by adding topical or systemic therapies, such as corticosteroids. Referring the patient to a dermatologist and/or allergist can be helpful and can help confirm the diagnosis. NPs must be vigilant in the diagnosis and management of various skin eruptions, but especially with drug-induced skin eruptions, as they are commonplace in any setting.
1. Reid JG, Gitlin MJ, Altshuler LL. Lamotrigine in psychiatric disorders. J Clin Psychiatry
2. Department of Veterans Affairs and Department of Defense. VA/DoD clinical practice guideline for management of bipolar disorder in adults. 2010. http://www.healthquality.va.gov
3. Calabrese JR, Sullivan JR, Bowden CL, et al Rash in multicenter trials of lamotrigine in mood disorders: clinical relevance and management. J Clin Psychiatry
4. Wang XQ, Xiong J, Xu WH, et al Risk of a lamotrigine-related skin rash: current meta-analysis and postmarketing cohort analysis. Seizure
5. Seo HJ, Chiesa A, Lee SJ, et al Safety and tolerability of lamotrigine: results from 12 placebo-controlled clinical trials and clinical implications. Clin Neuropharmacol
6. Handoko KB, van Puijenbroek EP, Bijl AH, et al Influence of chemical structure on hypersensitivity reactions induced by antiepileptic drugs: the role of the aromatic ring. Drug Saf
7. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders
. 5th ed. Washington, DC: American Psychiatric Association; 2013.
8. Goodwin GM, Haddad PM, Ferrier IN, et al Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol
9. Bobo WV. The diagnosis and management of bipolar I and II disorders: clinical practice update. Mayo Clin Proc
10. Błaszczyk B, Lasoń W, Czuczwar SJ. Antiepileptic drugs and adverse skin reactions: an update. Pharmacol Rep
11. Macy E, Ho NJ. Multiple drug intolerance syndrome: prevalence, clinical characteristics, and management. Ann Allergy Asthma Immunol
12. U.S. Food and Drug Association. Lamictal. FDA approved labeling text. 2010. http://www.fda.gov
13. Smith W. Adverse drug reactions – allergy? Side-effect? Intolerance. Aust Fam Physician
14. Lorberg B, Youssef NA, Bhagwagar Z. Lamotrigine-associated rash: to rechallenge or not to rechallenge. Int J Neuropsychopharmacol
15. Serrani Azcurra DJ. Lamotrigine rechallenge after a skin rash. A combined study of open cases and a meta-analysis. Rev Psiquiatr Salud Ment